Pharmacotherapy of Autoimmune Disorders
The medications in the following table are included in this policy:
Drugs by Therapeutic Drug Class
natalizumab (Tysabri®) may be considered medically necessary as a second line agent for the treatment of patients with:
All other uses of natalizumab are considered investigational.
Due to safety concerns, access to Tysabri® requires enrollment in the TOUCH registry maintained by the manufacturer. (See http://www.tysabri.com/safety-with-tysabri.xml.)
vedolizumab (Entyvio™) may be considered medically necessary as a second line agent for the treatment of patients with:
All other uses of vedolizumab are considered investigational.
Use of rituximab to treat ITP is considered not medically necessary if the criteria above are not met.
Use of rituximab to treat various types of cancer is covered in a separate medical policy 2.03.502 Monoclonal Antibodies for the Treatment of B-Cell Malignancies.
All other uses of rituximab are considered investigational.
interferon-β1a (Avonex® or Rebif®), or interferon-β1b (Betaseron®, Extavia®) may be considered medically necessary as first line agents for the treatment of relapsing forms of multiple sclerosis, when BOTH the following conditions are met:
All other uses of beta-interferons are considered investigational.
belimumab (Benlysta®) may be considered medically necessary for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) when BOTH the following conditions are met:
All other uses of belimumab are considered investigational.
Copaxone® 40mg (available as brand only) may be considered medically necessary as a second line agent for the treatment of relapsing forms of multiple sclerosis when BOTH the above conditions are AND and there has been documented inadequate response to or intolerance of the generic glatiramer 20mg.
All other uses of glatiramer are considered investigational.
All other uses of teriflunomide are considered investigational.
anakinra (Kineret®) may be considered medically necessary as a second line agent for its FDA-approved indication for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate, etanercept and adalimumab.
All other uses of anakinra are considered investigational.
tocilizumab (Actemra®) may be considered medically necessary as a second line agent for the FDA-approved indication for the treatment of moderate to severe active rheumatoid arthritis in patients that have inadequate response or intolerance to methotrexate, etanercept and adalimumab.
All other uses of tocilizumab are considered investigational.
All other uses of ustekinumab are considered investigational.
tofacitinib (Xeljanz®) may be considered medically necessary as a second line agent for its FDA-approved indication for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate, etanercept and adalimumab.
All other uses of tofacitinib are considered investigational.
alefacept (Amevive®) may be considered a medically necessary second-line agent for its FDA-approved indication of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy that have inadequate response or intolerance to etanercept and adalimumab, when the following criteria are met:
All other uses of alefacept are considered investigational.
All other uses of dimethyl fumarate are considered investigational.
All other uses of fingolimod are considered investigational.
apremilast (Otezla®) may be considered medically necessary for the treatment of adult patients with moderate to severe plaque psoriasis or psoriatic arthritis when ALL of the following criteria are met.
All other uses of apremilast are considered investigational.
All other uses of abatacept are considered investigational.
eltrombopag (Promacta®) may be considered medically necessary for the treatment of idiopathic thrombocytopenic purpura (ITP) or hepatitis C induced thrombocytopenia when all the following criteria are met:
All other uses of eltrombopag are considered investigational.
romiplostim (Nplate®) may be considered medically necessary for the treatment of idiopathic thrombocytopenic purpura (ITP) when all the following criteria are met:
All other uses of romiplostim are considered investigational.
etanercept (Enbrel®) may be considered a medically necessary first line TNF-α antagonist for its FDA-approved indications of:
• Moderate to severe rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis when the following conditions are met:
Biologic response modifier initiation criteria for plaque psoriasis:
Conventional therapy for Crohn’s disease: History of an adequate trial and treatment failure with at least two of the following:
Conventional therapy for Ulcerative Colitis: History of an adequate trial and treatment failure with at least three of the following:
Quantity Limits (If adequate response is not obtained at these doses, alternative drugs should be considered):
Use of TNF-α antagonists in patients with other arthropathies, autoimmune disorders or other conditions not listed above is considered investigational. Use for other rare conditions when all conventional therapies have been tried and failed or where they are clinically contraindicated may be considered on a case-by-case basis.
Use of TNF-α antagonists to treat milder plaque psoriasis is considered investigational. However, use in patients whose plaque psoriasis is refractory to treatment with recognized conventional therapies may be considered on a case-by-case basis.
The term “autoimmune disorders” covers a wide range of syndromes often involving damage to multiple organ systems. Since the advent of biologics and small molecule targeted therapies, a variety of pathways and specific points of intervention have been identified and drugs developed to modify the pathology that is damaging the patient. Since multiple diseases share common signaling pathways, it is not surprising that drugs and diseases often overlap, leading to the complex web of alternative therapies that are now available to physicians. This policy is an attempt to aggregate them all in a format that permits users to access and cross-reference the drugs in question by brand and generic name, target disease and pharmacologic drug class.
The diseases include a variety of inflammatory arthropathies such as rheumatoid and psoriatic arthritis and ankylosing spondylitis. Psoriasis, multiple sclerosis, and a large number of ultra-orphan diseases fall in this general category. The ones with large populations now have multiple drugs to choose from, while the orphans often lack a single FDA-approved therapeutic option. This poses a challenge to maintaining and updating medical policies.
Inflammatory arthropathies are a group of heterogeneous connective tissue disorders affecting the joints, which share certain common features such as inflammation and altered patterns of immune regulation. Those conditions at focus in this policy include rheumatoid arthritis (RA); and the spondyloarthropathies, psoriatic arthritis (PsA) and ankylosing spondylitis (AS).
Rheumatoid Arthritis (RA)
RA is a chronic, progressive, inflammatory, autoimmune disease affecting about 1% of the US adult population and occurs approximately 3 times more frequently in women than in men (ACR Subcommittee on Rheumatoid Arthritis Guidelines, 2002). Almost 80% of RA cases occur in patients between 35 and 50 years of age (Kavanaugh and Lipsky, 1996); usually a time of peak social productivity. The underlying cause of RA is unknown, but the disease is characterized by persistent inflammation of the synovium, cartilage loss, and bone erosion in peripheral joints, usually in a symmetric fashion. This inflammation is believed to be mediated by both B- and T-cells and a variety of cytokines (messenger proteins), including tumor necrosis factor-alpha (TNF-α). Research has shown that joint damage occurs within the first 2 years of symptoms and diagnosis and progresses rapidly if not treated. Although RA primarily affects the joints, it is a systemic disease and does cause systemic and extra-articular clinical features (e.g., fever, fatigue, anorexia, weight loss, and anemia), which contribute to the significant work disability and impaired quality of life which occur. Patients with RA also have earlier mortality than the general population averaging 7-10 years, primarily due to an increased risk of cardiovascular disease, infection, and lymphoma associated with more severe inflammation.
Psoriatic Arthritis (PsA)
PsA is characterized as a spondyloarthropathy associated with psoriasis. The true incidence is unknown, and is variably reported to occur in 6-42% (25% is considered a reasonable estimate) of patients with psoriasis, an immunologic skin disease which occurs in 2-3% of the general population. There is similarity in the histopathogenesis of PsA and RA, including the role of cytokines such as tumor necrosis factor alpha (TNF-α), although there are important differences as well. Several subsets of PsA have also been described. PsA is characterized by stiffness, both peripheral and spine inflammation and pain, joint deformities related to joint destruction, dactylitis, enthesitis (inflammation at insertion sites of tendons, ligaments, and joint capsule fibers), and psoriasis skin plaques. The course of PsA is variable, but the majority of patients develop a chronic progressive form of the disease resulting in joint destruction, unless treated effectively. Although less well characterized than in RA, similar levels of disability, decreased quality of life, increased co-morbidities, and premature mortality are now being noted in long term registry studies.
Other Spondloarthropathies (SpAs)
The spondyloarthropathies are a heterogeneous set of disorders characterized by axial skeletal involvement and frequent association with the HLA-B27 antigen. Ankylosing spondylitis (AS) is probably the most familiar spondyloarthropathy, which is characterized predominantly by progressive vertebral enthesitis and facet joint inflammation of the spine and sacroiliac joints, leading to eventual spine fusion and decreased range of motion, as well as peripheral joint synovitis, although much less than is seen in RA. Variations in incidence among different racial groups support the hypothesis of a genetic role in AS, as is also postulated in other arthropathies. In the United States, AS is believed to affect approximately 1-3 persons/1000, or about 350,000 to 1 million individuals.
While peripheral arthritis is commonly seen in association with psoriasis, approximately 20-40% of patients with PsA may have some degree of sacroiliitis with paravertebral ossification. The skin manifestations associated with the arthropathy are not necessarily widespread and may be localized.
About 20% of patients with inflammatory bowel disease may have evidence of sacroiliitis and some 20% of these patients may progress to spondylitis. The course of the spondylitis does not necessarily correlate with bowel inflammatory activity.
Psoriasis is a chronic, multifactorial, noncontagious skin disorder that affects about 2.1% of the U.S. population and 1-3% of persons worldwide. About 4.5 million, or 1 in 65, Americans have psoriasis. Onset is typically between the ages of 15 and 35 and prevalence is slightly greater in women. It is also more common in some ethnic groups (Caucasians) than others (African American or Asians). A genetic component has also been identified. There are several forms of psoriasis, but plaque psoriasis (or psoriasis vulgaris) is the most common form of the disease, affecting about 80% of psoriatic patients.
About 20-30% of people with psoriasis have cases that are considered moderate to severe (covering more than 3% of their body). Although not typically life-threatening, psoriasis can have a large impact on quality of life. Seventy-five percent of people with moderate to severe psoriasis report their disease has a moderate to large impact on their everyday lives. Patients with palmar-plantar disease may have less than 3% involvement, but often have debilitating and recalcitrant disease. Further, approximately 7% of psoriatic patients have concurrent arthritis (which may be particularly relevant to one’s choice of therapy).
Psoriasis is a chronic immune-mediated inflammatory disease characterized by T-cell activation and accumulation in the epidermis and dermis, leading to abnormal differentiation and hyperproliferation of keratinocytes. Recent advances in the understanding of the cellular mechanisms underlying psoriasis have given rise to a generation of highly targeted biotechnologies for this indication.
As the severity of psoriasis ranges from mild to severe, with or without concurrent arthritis, available treatments lie along a spectrum from minimally invasive with a low risk of systemic side effects, to systemic therapy with a risk of potentially severe side effects. Non-invasive, topical treatments may also have significant side effects; for example, topical corticosteroids applied to large areas of skin may result in significant levels of systemic absorption. Many treatments have a cumulative toxicity potential, but the benefit of prolonged remissions makes the use of the more potent treatments relatively attractive.
Inflammatory Bowel Diseases (IBD)
This diagnosis grouping includes Crohn’s disease (CD) and ulcerative colitis (UC). Unlike UC, CD is not limited to the colon and can manifest anywhere in the GI tract. Therefore, while UC can be eliminated by performing total colectomy, CD cannot. CD is an idiopathic, chronic inflammatory disease of the gastrointestinal tract affecting primarily the small and large intestine. CD is caused by a dysregulation of the normal gut immune response, ultimately creating a chronic inflammatory state. TNF-α is thought to be at the center of a complex cascade of immune mediated events that result in the pathological manifestations of the disease. The main presenting symptoms of CD include: abdominal pain, diarrhea, rectal bleeding, malaise, fever, weight loss, and right-lower-quadrant pain and tenderness. Severe complications of the condition include fistulas, strictures, intra-abdominal abscesses, and nutrient malabsorption. CD and UC have overlapping features and as such are collectively known as inflammatory bowel diseases. Although the presentation of UC is usually different than CD because it is limited to the rectum and colon, their overlapping characteristics can make differential diagnosis very difficult. However, it is important to note the differences, since treatments that are successful in UC will not necessarily work as well in CD.
Miscellaneous Autoimmune Diseases
TNF inhibitors, rituximab and various other agents have been used off-label to treat a variety of autoimmune diseases. Most of these represent significant unmet medical needs.
Systemic lupus erythematosus (SLE)
Systemic lupus erythematosus (SLE) is a chronic, complicated, progressive autoimmune disease impacting multiple organ systems. It is a condition characterized by auto-reactive b-cells. Autoantibody production from such abnormal b lymphocyte function leads to chronic inflammation and cellular, tissue and organ damage. Diverse in presentation, patients with SLE experience mild to life-threatening manifestations and unpredictable clinical course of exacerbations and remissions. As symptoms are non-specific, the identification of SLE is often-times delayed. It has been reported that patients visit a mean of three different physicians and an average of 4 years after the onset of symptoms before a correct diagnosis is reached.
The mucocutaneous (rash), articular (arthritis), serosal (pleuritis, pericarditis), renal (proteinuria) and neurologic (seizures, psychosis) clinical features, as well as hematologic and immunologic laboratory findings, incorporated in the American College of Rheumatology SLE diagnosis classification criteria reflects the heterogeneity of the disease. Most commonly involved organs include the skin, musculoskeletal, renal, nervous cardiovascular and pulmonary systems. Over 75% of SLE patients have debilitating, generally non-fatal mucocutaneous (rash) and musculoskeletal involvement (arthritis). A smaller SLE population (50%-66%) is afflicted with renal disorders, and is associated with poorer outcome and mortality. About 2/3 of SLE patients also present with varying severity of neuropsychiatric manifestations ranging from mood disorders, anxiety, psychosis to seizures. Other less common but serious manifestations include serositis (16 to 64%), neurological disorders (9 to 36%), and immune-mediated cytopenias (4 to 43%). Depression is common among people with chronic autoimmune disease. Overall, SLE patients have a 2-5 times greater mortality rate.
As endogenous female sex hormone is identified to have a role in SLE development, SLE is found primarily in women (90% of SLE population are female, 6-10 female:1 male), typically 15-44 years of age. In the US, more than 300,000 people have SLE and an annual incident rate of 15,000. 4 million people are impacted worldwide.
While SLE patients have at least twice the mortality risk relative to the general population, survival rate at 15 years improved dramatically from 50% in the 1950s to currently greater than 80%. Most common causes of death are cardiovascular disease, infections, renal disease and complications due to SLE disease activity.
In addition to gender, ethnicity has an influence on the development of SLE. Mestizo, indigenous Americans, Blacks and Asians have more severe SLE disease and poorer clinical progression. Blacks are three times more likely than Caucasians to have SLE. Asian and African American SLE patients develop renal disease more frequently than those of European descent (60-70%, 50%, 20-30%, respectively).
Systemic Lupus Erythematosus (SLE) is characterized by auto-reactive B-cells. Autoantibody production from such abnormal B lymphocyte function leads to chronic inflammation. Autoantibody complex, cytokines and complement activation represent mediators of tissue damage in SLE patients. Anti-nuclear antibody (ANA) is found present in more than 90% of patients. Those positive are more likely to have active lupus associated with B cell dysfunction. Anti-dsDNA, a type of anti-nuclear antibody (ANA), is one of the diagnosis criteria established by the American College of Rheumatology and is monitored as gauge of SLE disease response to treatment. Consistent with existing pathophysiology, inhibition of BLyS, an endogenous protein responsible for B-cell homeostatsis, decreases autoreactive B-cell activity and serological changes. Transgenic animals overexpressing BLyS have lupus-like syndrome, increased immunoglobulins and immune complex depositions. BLyS is also found elevated in human autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Sijogen’s.
Most patients present with generalized symptoms of fatigue, fever, anorexia, weight loss, photosensitivity, malar rash, oral ulcers, arthralgia and hair loss. Incompletely controlled SLE can progress to end-stage organ involvement; SLE activity of 60% of SLE patients is found to worsen within 2-7 years of diagnosis. Irreversible cellular and tissue damages can accumulate to result in life-threatening renal, cardiac, pulmonary, CNS and hematological system toxicities. The subsequent development of pleuritis, pericarditis, stroke, seizure, nephritis, vasculitis, anemia, thrombocytopenia and other blood dyscrasias present significant mortality and morbidity risks.
Aside from these autoimmune mediated disease manifestations, SLE patient are in high risk for infections of the respiratory and urinary systems, cardiovascular diseases, hematological and solid tumors, maternal and fetal morbidity and mortality (spontaneous abortions, pre-eclampsia, intrauterine growth impairment, premature birth). Most common causes of death are infections, renal disease, cardiovascular disease and complications due to SLE disease activity.
Idiopathic Thrombocytopenic Purpura (ITP)
Idiopathic Thrombocytopenic Purpura (ITP) is an autoimmune disorder characterized by destruction of normal platelets due to unknown stimulus and a resulting risk of severe bleeding complications. Recent update by International Working Group (IWG) consensus panel set the platelet count threshold as less than 100,000 per µL. The initiating event of ITP is unclear and various mechanisms of platelet destruction may be important. IgG autoantibodies on the platelet surface can cause platelet uptake and destruction by reticuloendothelial phagocytes. T-cell mediated cytotoxicity against megakaryocytes and platelets may cause thrombocytopenia. In addition to increased platelet destruction, the production of platelets is often decreased in ITP.
Adult ITP has an annual incidence of approximately two cases per 100,000. It is estimated in the United States there are 100 patients with ITP per one million people or approximately 30,000 total and 15,000 with a chronic form of ITP assuming the population is 300 million. Adult ITP is more likely than childhood ITP to be chronic. Spontaneous remission occurs in more than 80% of cases in children but is uncommon in adults. As a result, evidence based treatment guidelines differ between adult and children. For specific treatment recommendations in children with ITP, please refer to the ASH 2011 guideline “Section 1: ITP in children”. The incidence rate appears to increase with age, with the highest age-specific incidence in patients older than 60 years of age. The female-to-male ratio of ITP patients is bimodal, being 1.9 women for each man in ages less than 50 and 1.2:1 in ages 65 and older. There is no apparent prevalence difference between African Americans and whites. Intracranial hemorrhage represents the most serious complication of ITP. The mortality rate from hemorrhage is approximately 1% in children and 5% in adults. In patients with severe thrombocytopenia, predicted five-year mortality rates from bleeding are significantly raised in patients older than 60 years versus patients younger than 40 years, 47.8% versus 2.2%, respectively.
Pyoderma gangrenosum is an inflammatory disease with dermatologic manifestations including painful ulcerations with erythematous borders. It is presumed to be autoimmune in origin, though the mechanism is not well understood. Lesions usually develop at sites of minor skin injury, usually on the lower extremities. These lesions can grow in size and become necrotic. Underlying fasciitis may occasionally develop from them. Some patients develop pustular, bullous or vegetative lesions. Other common sites are colostomies and paraneoplastic lesions in patients with hematologic malignancies. Progress of the lesions is highly variable, and patient response to treatment is heterogeneous. Obesity, diabetes or edema may be contributing factors.
Due to the infrequent occurrence and heterogeneity of pyoderma gangrenosum, the treatment approach is empiric and patient-specific. First-line options include topical tacrolimus, nicotine, and 5-ASA, systemic corticosteroids and immunosuppressant agents such as azathioprine, cyclosporine, methotrexate and mycophenolate. When these approaches fail, biologic therapy is usually tried. Successful treatment with TNF inhibitors (etanercept, adalimumab, infliximab) has been reported. Response to ustekinumab and various investigational interleukin inhibitors has also been reported. Surgical management is another option.
Wegener’s Granulomatosis and Microscopic Polyangitis
Wegener’s granulomatosis (WG) is an autoimmune vasculitis that may affect various internal organs and can be potentially life-threatening. Symptoms vary and can mimic a variety of other diseases, making it difficult to diagnose. These include rhinitis, glomerulonephritis, pulmonary nodules and hemorrhage, neuropathies, gastrointestinal symptoms and various other inflammatory manifestations. The disease can occur at any age, usually in adults.
WG can be recognized by the distinctive triad of granulomatous inflammation, necrosis, and vasculitis of the respiratory tract. Vasculitis in other regions is also common. It can follow a varied clinical course that is strongly influenced by treatment. Untreated, generalized WG is usually lethal. Historically, treatment with immunosuppressants has been used. Glucocorticoids and cyclophosphamide have been a standard therapy, but this is limited by cyclophosphamide toxicity. If remission is achieved, less toxic agents such as azathioprine may be employed for maintenance.
The U.S. Food and Drug Administration (FDA) has approved rituximab in combination with glucocorticoids, to treat patients with WG and microscopic polyangiitis (MPA). Both of these diseases affect people of all ages and ethnicities, and both genders. The causes of these disorders are unknown, and both are considered orphan diseases because they each affect less than 200,000 people in the United States.
It is currently thought that multiple sclerosis (MS) is the result of a combination of factors including immune response, genetics, infection, and environmental issues. MS is characterized by the destruction of the myelin sheath that surrounds axons of the central nervous system (CNS) and eventual axonal damage. This is believed to be an autoimmune attack against myelin and the myelin-producing oligodendrocytes. There is an associated inflammatory response involving B-cells, T-cells, macrophages, antibodies, and complement. The myelin sheath is replaced by sclerotic plaques. The damage to the myelin sheath can delay or halt nerve impulses. Axonal damage leads to loss of nerve impulses.
An estimated 250,000 to 400,000 cases exist in the United States. In 2000, the estimated prevalence was 191/100,000 Caucasians in the United States, with an incidence rate of 7.3/100,000 person-years at risk. Diagnosis usually occurs when patients are between 20 and 50 years of age. The disease is more prevalent: 1) further away from the equator; 2) in Caucasians; and 3) in women. Other risk factors include Epstein-Barr virus exposure, vitamin D deficiency, and smoking.
MS usually follows one of the following four disease courses, but individual presentation can vary quite widely.
Progressive-relapsing MS (PRMS): initially presents as PPMS with steady disease progression, but later experiences acute attacks with followed by partial recovery. This is only seen in approximately 5% of MS patients.
Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
The American College of Rheumatology (ACR) has established clinical guidelines for the treatment of rheumatoid arthritis (RA). While both non-pharmacologic (e.g., patient education, exercise, and physical and occupational therapy) and pharmacologic therapies are recommended, the mainstay of RA treatment is pharmacologic therapy. Pharmacologic management often consists of nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs) (including biologic response modifiers/cytokine antagonists), and/or corticosteroids. Because of the evidence showing that joint damage can occur early in the disease process, physicians are now encouraged to treat patients more aggressively earlier by initiating a DMARD (or combinations of DMARDs) within 3 months of diagnosis.
Emerging evidence also suggests that the DMARD subclass of tumor necrosis factor-alpha (TNF-α) antagonists retard radiographic progression of the disease better than methotrexate (MTX), particularly in patients with rapidly progressive disease. The predictive risk factor found to be most associated with this subset of patients was a CRP ≥4.1 mg/dl. Other predictors are currently being investigated. This should lead to improved ability for the clinician to determine the best DMARD for an individual patient; however, the choice will continue to be influenced by numerous factors, including but not limited to relative efficacy, convenience of administration, adverse effects, monitoring requirements, comorbidities, and cost. Abatacept and rituximab have also gained labeling regarding ability to inhibit progressive structural damage.
Pharmacologic therapy combined with a physical rehabilitation program is the most effective available treatment for psoriatic arthritis (PsA). As with RA, early initiation of pharmacologic therapy is needed to avoid joint damage and disability.
NSAIDs have customarily been used in milder disease along with corticosteroids or traditional DMARDs. Moderate to severe disease requires the use of traditional DMARDs such as MTX, sulfasalazine, or the anti-TNF agents. Azathioprine and cyclosporine are rarely used. Retinoids, phototherapy, and topical and systemic corticosteroids have also been used to treat the skin manifestations of PsA. In January 2002, etanercept, a TNF-α inhibitor became the first therapy to be approved for the indication. Adalimumab has also recently received FDA-approval for this indication. Additionally, infliximab has been demonstrated effective for this condition in at least one randomized, double-blind, controlled clinical trial. FDA has since approved the newer TNF-α inhibitors certolizumab pegol and golimumab for this indication. More recently, the IL12/IL23 inihbitor ustekinumab and the phosphodiesterase 4 inhibitor apremilast are now approved.
Treatment of mild spondyloarthropathy may be benefited by symptomatic therapy with NSAIDs, corticosteroids, or sulfasalazine. These agents have shown to have little clinical benefit in patients with moderate to severe or progressive disease. The paucity of treatment options contrasts with the treatment of RA where there are several different categories of DMARDs (disease-modifying anti-rheumatic drugs) that are used alone or in combination to try and alter the natural history of the disease. Like PsA, etanercept became the first therapy approved by the FDA for the treatment of AS, followed by infliximab and adalimumab.
Topical therapy, usually corticosteroids, is recommended as first-line treatment in psoriasis because these products are easy to administer, inexpensive, and safe. However, application to large areas of involvement can be time-consuming, expensive, and messy. Most patients with moderate to severe disease will not achieve clearance or long-term remission. Tachyphylaxis may also develop with long-term use of topical corticosteroids. In patients whose moderate to severe psoriasis fails topical therapy, the therapeutic options that remain are systemic agents, phototherapy and biologics.
Approved systemic agents (methotrexate, cyclosporine, and acitretin) are highly effective in the treatment of psoriasis; however, these therapies have limitations due to serious toxicities that require monitoring. Methotrexate can cause hepatotoxicity. Methotrexate is also associated with bone marrow toxicity, severe pulmonary toxicity, and serious drug-drug interactions (e.g., trimethoprim-sulfamethoxazole). Cyclosporine is nephrotoxic, and can cause interstitial fibrosis and renal tubular atrophy in patients treated for more than 2 years. Hypertension, laboratory abnormalities (electrolytes, liver function tests, lipids), and numerous drug-drug interactions are also among the problems associated with cyclosporine. Because methotrexate and cyclosporine are potent immunosuppressive drugs, patients are at increased risk of infections and malignancies, including skin cancers and lymphoproliferative disorders. Like all retinoids, acitretin is highly teratogenic, posing a long-lasting risk (up to 3 years) in women of childbearing potential. Elevation in liver function tests, hyperlipidemia, and mucocutaneous reactions are additional adverse events associated with acitretin. Systemic corticosteroids are generally avoided as they may be associated with severe exacerbations, both during and after treatment.
Phototherapy (e.g., UVB, narrowband UVB, PUVA) is used for patients who fail topicals or those with disease too extensive for topical therapy. Phototherapy can be effective for many patients, but it is inconvenient and time-consuming, as frequent office or clinic visits are required and the availability of specialized phototherapy clinics may be limited. Cumulative exposure to PUVA is associated with an increased risk of squamous cell carcinoma and malignant melanoma.
Various other strategies using traditional therapies have also been used to maintain remission and decrease the risk of cumulative end-organ toxicities. Rotational therapy involves the use of a therapy for some time and then switching to another form of therapy. Combination therapy uses low-dosages of different treatments concurrently to minimize toxicity and enhance efficacy. Traditionally, these strategies usually involve topicals, phototherapy, and systemics in various combinations.
Biologic agents have been shown effective for many patients in randomized, double-blind, placebo-controlled clinical trials, but there are few head-to-head clinical trials comparing these agents with traditional therapies. NBUVB continues to appear a very effective therapy in terms of achievement of ≥75% response, global assessment (“clear or almost clear”), and length of remission. While the long-term risks of PUVA, methotrexate, and cyclosporine use in psoriatic patients have become more clearly identified, these data are not available for the biologics in this population. The new biologic agents are clearly more widely available and convenient than the mainstay of psoriasis therapy, NBUVB, which may require anywhere from 30-100 outpatient visits to specialized facilities per year. On the other hand, biologics are all administered by injection, making them less convenient than systemic oral therapy.
Infliximab (Remicade®) is approved for the treatment of adults with chronic severe plaque psoriasis who are candidates for systemic therapies and clinical trial results for adalimumab (Humira®), Remicade and etanercept (Enbrel®) have been published. Of these, three Humira studies added enough new information to warrant off-label use consideration. In the first multicenter, randomized, double-blind, placebo-controlled study, 147 patients received Humira 80 mg at week 0, then 40 mg every other week beginning week 1, Humira 80 mg at week 0 and 1, then 40 mg every week beginning at week 1, or placebo for 12 weeks, after which placebo patients were crossed over to Humira 40 mg every other week in a 48-week open label extension trial. At week 12, 53% of patients taking Humira every other week, 80% of patients taking Humira weekly, and 4% of patients taking placebo achieved 75% improvement in Psoriasis Area and Severity Index score (P<0 .001). Responses were sustained for 60 weeks. Humira was safe and well tolerated in this population.
In the Phase III REVEAL study (Randomized Controlled Evaluation of adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis TriAL), 1,212 patients with moderate to severe chronic plaque psoriasis were randomized to treatment with Humira 80 mg at week 0, then 40 mg every other week beginning at week 1 or placebo. The trial was comprised of 3 periods, a 16-week, double-blind period for assessment of initial response; a 17-week open-label sustained response period, in which responders to either treatment (those achieving a PASI-75) received Humira 40 mg every other week; and a final 19-week, double-blind loss of response period, in which patients receiving Humira throughout the previous 2 study periods were re-randomized to either Humira every other week or placebo. In the initial response phase, more Humira-treated patients achieved a PASI-75 compared to those receiving placebo beginning at week 4 and at every visit throughout the 16-week evaluation period. At week 16, 71% of Humira- and 6.5% of placebo-treated patients achieved a PASI-75 (P<0.001). In Humira responders, mean PASI scores were maintained throughout the subsequent maintenance of response period (weeks 16-33) of the study. In the last period of the study examining loss of response, 28.4% of patients re-randomized to placebo lost response by week 52 compared to 4.9% of patients maintaining Humira (P<0.001). Humira was generally well tolerated and no unexpected adverse events were observed over the 52 weeks of the trial.
In a second Phase III trial, CHAMPION (Comparative Study of HUMIRA vs. Methotrexate vs. Placebo In PsOriasis Patients), 271 patients were randomized to treatment with Humira 80 mg at week 0, then 40 mg every other week beginning at week 1 (n=108), methotrexate 7.5 mg x 2 weeks, 10 mg x 2 weeks, then 15 mg orally (n=110), or placebo (n=53) for a total of 16 weeks. At week 16, more Humira-treated patients achieved a PASI-75 response (80%) than patients receiving either methotrexate (36%, P<0.001) or placebo (19%, P<0.001). Similar results were observed for PASI-90 response and PGA “clear” or “minimal” response. Humira was generally well-tolerated, with a safety profile similar to that known for an arthritis population.
In September 2009, the FDA approved the use of ustekinumab to treat plaque psoriasis. Ustekinumab is a human IgG1қ monoclonal antibody that binds to the shared p40 subunit of interleukins 12 and 23, blocking signaling of their cognate receptors. It is known that IL-12 and IL-23 plays important roles in the pathogenesis of psoriasis. IL-12 causes differentiation of CD4+ T cells to interferon-gamma (IFN-gamma)-producing T helper 1 (Th1) cells, while IL-23 induces differentiation to IL-17-producing pathogenic Th17 cells. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12 β1
The evidence of efficacy consists mainly of two pivotal trials (PHOENIX I and PHOENIX II) submitted for FDA approval. Both studies showed robust clinical result against placebo. The primary endpoint for both studies was the proportion of patients achieving a PASI 75 in the 12 week placebo-controlled trial. Both the 45mg and 90 mg groups achieved statistically significantly higher PASI 75 rate compared to placebo (67.1%, 66.4%, 3.1%, respectively; each p<0.0001 vs. placebo). Both studies also showed favorable secondary endpoint results for PGA score and DLQI vs. placebo. Ustekinumab was found more efficacious compared to etanercept during a Phase III, multi-center, active controlled trial with 930 patients (ACCEPT trial). For the primary efficacy endpoint of PASI 75 at week 12, a greater proportion of patients treated with ustekinumab 45mg and 90mg achieved a PASI 75 compared to those receiving etanercept 50mg.
More recently, phosphodiesterase 4 inhibitor apremilast has been now approved for moderate to severe plaque psoriasis. Two multicenter, randomized, double-blind, placebo-controlled trials (PSOR-1 and PSOR-2) enrolled a total of 1257 subjects with moderate to severe plaque psoriasis. In both studies, subjects were randomized 2:1 to apremilast 30 mg BID or placebo for 16 weeks. Primary endpoints were the proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved a sPGA score of clear (0) or almost clear (1) at Week 16. Approximately 30% of all subjects had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. A total of 18% of subjects had a history of psoriatic arthritis. Approximately 33% of patients receiving apremilast in PSOR-1 achieved a PASI-75 (vs 5% on placebo), and 29% of apremilast patients in PSOR-2 (vs 6% on placebo). In all groups, approximately 2/3 of patients achieving PASI-75 also had sPGA scores of clear (0) or almost clear (1).
Crohn’s Disease (CD)
The American College of Gastroenterology indicates current therapeutic recommendations depend on disease location, disease severity, and the presence of disease-associated complications. Pharmacologic approaches include various 5-aminosalicylates (5-ASAs), corticosteroids, and immunosuppressants. While the effectiveness of the 5-ASAs is less than corticosteroids, their side effect profile is more favorable. Azathioprine and sulfasalazine are also associated with clinically significant long-term toxicity, according to the National Cooperative Crohn’s Disease Study. Azathioprine, sulfasalazine, and prednisone have not been demonstrated to prevent recurrence of disease flares.
Surgical resection is a common occurrence in CD, with up to 57% of patients requiring at least one surgery in any given year. Within 10 years of disease onset, 71% of patients undergo this therapy.
Clinical trials with infliximab (Remicade) in patients with moderate to severe CD have shown that Remicade significantly reduces symptoms, improves quality of life, provides endoscopic evidence of mucosal healing, and reduces recurrence rates allowing for fewer hospitalizations and invasive procedures. Additionally, patients with fistulizing disease were able to achieve a reduction in the number of draining enterocutaneous and rectovaginal fistulas.
The safety and efficacy of adalimumab (Humira) for the induction and/or maintenance of remission in patients with moderately to severely active CD (Crohn’s Disease Activity Index [CDAI] ≥220 and ≤450) was evaluated in four randomized placebo-controlled studies. Two of these studies evaluated Humira for induction of remission (defined as a CDAI <150), one study in patients who were TNF antagonist naïve (CLASSIC-I) and the other in patients who had lost response or were intolerant to Remicade (GAIN). Two of these studies evaluated Humira for maintenance of remission, both studies in patients who were TNF antagonist naïve (CLASSIC-II and CHARM).
In CLASSIC-I, 299 patients with moderately to severely active CD, including patients with draining fistulas, were randomized to two subcutaneous injections at Weeks 0 and 2 with Humira 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. Enrollees were also able to maintain existing therapy with immunomodulatory agents, corticosteroids, and/or aminosalicylates. The primary efficacy endpoint was induction of remission (CDAI <150) at Week 4. The rate of remission was significantly higher in the 160 mg/80 mg group (36%, p=0.001), but not for the 40 mg/20 mg (18%, p=0.36) or 80 mg/40 mg (24%, p=0.06) groups compared with placebo (12%). Injection site reactions occurred more frequently in Humira-treated patients, otherwise adverse events occurred at similar frequencies in all four treatment groups.
In GAIN, 325 patients with moderately to severely active CD who were intolerant of, who had lost response, or who had an inadequate response to Remicade were randomized to two subcutaneous injections at Weeks 0 and 2 with Humira 160 mg/80 mg or placebo. Primary efficacy endpoint was induction of remission (CDAI <150) at Week 4. Clinical response (decrease in CDAI score ≥70 or 100) at Week 4 was also assessed. More Humira-treated patients (21%, p<0.001) achieved clinical remission compared to those treated with placebo (7%). More Humira-treated patients (52%, p<0.01) achieved a clinical response-70 compared with the placebo group (34%).
A total of 276 patients participating in CLASSIC-I enrolled in CLASSIC-II and received open-label Humira 40 mg subcutaneously at Weeks 0 (Week 4 of CLASSIC-I) and 2. Those patients (n=55) in remission at both Week 0 and Week 4 were re-randomized to Humira 40 mg QOW, 40 mg QW, or placebo for 52 additional weeks. Patients who were not in remission at both Weeks 0 and 4 were treated with open-label Humira 40 mg QOW. These patients were allowed to have their dose increase to 40 mg QW for non-response or disease flare. The re-randomized patients were also allowed to “escape” into this open-label arm with disease flare. The primary efficacy endpoint was maintenance of remission (CDAI <150) in randomized patients through week 56. Of the 55 patients randomized at Week 4, a greater proportion receiving Humira (79% of the Humira 40 mg QOW group and 83% of the 40 mg QW group, both p<0.05) were in remission compared to the placebo group (44%). Of 204 patients entering the open-label arm, 46% were in remission at Week 56. Humira was generally well-tolerated.
In CHARM, a total of 854 patients with moderately to severely active CD were treated with open-label Humira 80 mg at Week 0 followed by 40 mg at Week 2 as induction therapy. At Week 4, patients were stratified by clinical response (decrease of CDAI ≥70) and randomized to double-blind treatment with subcutaneous Humira 40 mg QOW, Humira 40 mg QW, or placebo weekly for 52 additional weeks. The proportion of randomized clinical responders achieving clinical remission at Week 26 and 56 were coprimary endpoints. At Week 4, 499/854 (58%) of patients achieved a clinical response-70 and were randomized to Humira or placebo. The percentage of randomized responders in remission was significantly greater in the Humira 40 mg QOW and 40 mg QW groups compared to the placebo group at Week 26 (40%, 47%, and 17%, respectively; p<0.001) and at Week 56 (36%, 41%, and 12%, respectively; p<0.001). No significant differences in efficacy were observed between the two active treatment groups. Patients who did not achieve clinical response after 12 weeks were unlikely to achieve response. The safety profile for Humira was consistent with previous experience with the drug. More patients receiving placebo (13.4%) discontinued treatment for an adverse event than those receiving Humira (6.9% in the 40 mg QOW and 4.7% in the 40 mg QW group).
Two randomized controlled phase 3 trials, PRECiSE 1 and PRECiSE 2, demonstrated the safety and efficacy of Cimzia 400 mg SC at Weeks 0, 2, 4 and then every four weeks versus placebo for up to 24 weeks. In the induction study, patients who had C-reactive protein (CRP) levels >10 mg/L at baseline who were treated with certolizumab had higher response rates than placebo-treated patients (37% versus 26%; p=0.04) at Week 6. In the overall population, response rates were significantly higher with certolizumab vs. placebo (23% versus 16%; p=0.02). There were no significant differences in remission rates at Week 6 or 26 between certolizumab and placebo. Overall, certolizumab was well tolerated. The other trial investigated the efficacy of maintenance therapy in patients that had completed a standard induction course. In this study 64% of all initially enrolled patients achieved a clinical response (decrease in CDAI ≥150) at 6-weeks. Certolizumab produced significantly better maintenance of clinical response than placebo through Week 26 (62% versus 34%, p < 0.001) in patients with CRP ≥ 10 mg/L. Maintenance treatment with CIMZIA showed significantly better remission rates than placebo at Week 26 (48% versus 29%, p < 0.001) in the ITT population. The adverse event profiles observed in these studies was similar to that seen with other anti-TNF agents.
The ENCORE, ENACT-1 and ENACT-2 trials found that the use of Tysabri in adults with moderate to severe CD significantly increased the percent of patients with a clinical response and those in clinical remission. In patients shown to be responders after 12-weeks of induction therapy, response rates and remission rates were significantly greater with Tysabri.
The percent of patients with sustained remission after withdrawal of oral steroids was also significantly greater with Tysabri versus placebo at Weeks 36 and 60. For assessment of quality of life, patients treated with Tysabri experienced statistically and clinically significant improvements in both general measures (SF-36) and disease specific measures (IBDQ) beginning at Week 24 and continuing through Week 60 compared with placebo. From Week 24 through 60, patients treated with Tysabri had quality of life scores consistent with remission.
A 12-week trial in CD patients found a significantly higher incidence of headache, nasopharyngitis, and hypersensitivity-like reactions at Week 12. Development of anti-natalizumab antibodies at any post-baseline visit through Week 12 was more common with natalizumab vs. placebo. Exacerbation of CD and discontinuations due to adverse events were more common with placebo than with Tysabri at Week 60. There was a higher incidence at Week 60 of influenza with natalizumab compared to placebo. Viral infections were more common with natalizumab compared to placebo. At Week 12, there was a higher incidence of hypersensitivity reactions during infusion with natalizumab versus placebo.
Tysabri was initially approved for the treatment of multiple sclerosis in November 2004. It was withdrawn from the market by the manufacturer in February 2005 after three patients in clinical trials developed progressive multifocal leukoencephalopathy (PML). The FDA stopped clinical trials for the product in February 2005. Following no new cases of PML, the FDA allowed Tysabri to return to the market in June 2006 with the requirement of a risk minimization program to be in place to limit use. Patient registration and periodic follow-up is also required. In August 2008, two additional cases of PML were reported in European Tysabri patients, bringing the total to five. Both patients were taking the drug for multiple sclerosis. Both had received at least one year of therapy and neither was receiving any other biologic immunomodulator concurrently. The implications for Crohn’s patients remain unclear.
The TOUCH® program requires distribution of Tysabri only through centralized or specialty pharmacies that have registered and follow the strict requirements of patient assessment, monitoring, education, and follow-up. Tysabri is currently only approved for monotherapy as it is unclear if the risks of PML increase with concurrent use of other immunosuppressives. Notably, the use of concomitant immunosuppressives was associated with PML in three cases, of which two patients were being treated for MS and one for CD.
The safety and efficacy of vedolizumab (Entyvio™) were evaluated in 3 Phase III, double blinded, placebo controlled, multicenter, randomized clinical trials—two in Crohn’s diasease and one in ulcerative colitis. There were total of 3,326 patients participated in these trials. There were high discontinuation rates across all arms of the trials (51% to 62%), most often for a lack of efficacy (59% to 69%). Discontinuation did not appear to be different between placebo and drug arms and intention-to-treat efficacy analysis was performed to generate the data.
GEMINI 2 trial shows efficacy of vedolizumab in patients with Crohn’s disease. The study populations had a mean duration of disease of 9 (SD: 7.8) years and 51% of patients were on glucocorticoids with median prednisone dose of 20 mg. At week 6, 15% of patients in the vedolizumab arm and 7% of the patients in the placebo arm had a clinical response (p=0.02). In the maintenance trial, which included only those responded to the induction therapy, 39% of those assigned to VDZ Q8W were in clinical remission at week 52, compared with 22% assigned to placebo (p<0.001). Clinical remission is defined as CDAI score ≤150. Durable clinical remission was 21% in the VDZ Q8W group compared with 14% in the placebo group (p=NS). Glucocorticoid-free remission was 32% in the VDZ Q8W compared with 16% in the placebo group (p=0.02).
GEMINI 3 trial tested the efficacy of vedolizumab in patients with Crohn’s disease but it was discontinued after the induction phase due to lack of efficacy. The study authors explained that the statistically non-significant effect of vedolizumab as induction therapy could be related to the baseline disease severity and heavily pretreated disease state in the study population. Only the abstract is available on GEMINI 3 trial.
During the trial, 56 of 1434 (4%) of patients treated with vedolizumab had detectable anti-vedolizumab antibody at anytime during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.
In April 2013, Feuerstein, et al., reported results of a systematic review of treatment recommendations by international guidelines for Crohn’s disease. Of the 89% of guidelines that graded evidence, only 23% of treatment recommendations were supported by level A evidence, and 28% by level B; thus, approximately half the recommendations were based on lower quality evidence or expert opinion. This reflects the difficulties encountered in treating this perplexing disease. Policy updated to include new labeled indication of golimumab to treat ulcerative colitis. A full review of this policy will be scheduled later in the year.
August 2013: As the most recent US and European guidelines for the treatment of adults with Crohn’s disease call into question the efficacy of 5-ASAs for induction or maintenance of remission for this condition, their use prior to approval of a TNF-α inhibitor is no longer a requirement in Crohn’s disease. The efficacy of 5-ASAs for induction or maintenance of remission in ulcerative colitis remains established and use prior to approval of a TNF-α inhibitor remains a requirement in this condition.
However, several new themes or trends have been identified and should be followed. These included a potential new therapeutic goal of “deep remission”, defined as a Crohn’d disease activity index (CDAI) score <150 and complete mucosal healing on endoscopy. A Crohn’s Disease Digestive Damage Score (Lémann score) has been developed to measure cumulative bowel damage in patients with this condition. Similar to the Sharp score for assessing joint damage in rheumatoid arthritis (RA), the Lémann score may be used to assess the effect of various pharmacological therapies, function as a clinical trial endpoint, and allow better identification of high-risk patients in regard to identification or progression of bowel damage. Also analogous to RA, there is momentum growing in Crohn’s for use of disease modifying agents (e.g., TNF-α inhibitors) early in the disease course to avoid later complications and need for surgery, particularly in patients with poor prognostic factors. Combination therapy with an immunosuppressive and a TNF-α inhibitor is also promising. However, robust supporting scientific evidence for these emerging trends is still lacking. New compounds currently in phase II and/or III development for use in IBD include ustekinumab (Stelara®), tofacitinib (Xeljanz), and vedolizumab.
Ulcerative Colitis (UC)
The safety and efficacy of Remicade were assessed in two randomized, double-blind, placebo-controlled clinical studies in 728 patients with moderately to severely active ulcerative colitis (UC) with an inadequate response to conventional oral therapies.15 In both studies, patients were randomized to receive either placebo, 5 mg/kg Remicade or 10 mg/kg Remicade at Weeks 0, 2, 6, 14 and 22.
Patients in study 1 had failed to respond or were intolerant to oral corticosteroids, 6-mercaptopurine (6-MP), or azathioprine (AZA). Patients in study 2 had failed to respond or were intolerant to the above treatments and/or aminosalicylates. Similar proportions of patients in studies 1 and 2 were receiving corticosteroids (61% and 51%, respectively), 6-MP/azathioprine (49% and 43%) and aminosalicylates (70% and 75%) at baseline. More patients in study 2 then 1 were taking solely aminosalicylates for UC (26% versus 11%, respectively). Clinical response was defined as a decrease from baseline in the Mayo score by 30% and 3 points, accompanied by a decrease in the rectal bleeding subscore of 1 or a rectal bleeding subscore of 0 or 1.
In both studies, greater percentages of patients in both Remicade groups achieved a clinical response, a sustained clinical response (response at both Weeks 8 and 30), clinical remission and other assessed clinical outcomes than in the placebo group. Of patients on corticosteroids at baseline, greater proportions of patients in the Remicade treatment groups were in clinical remission and able to discontinue corticosteroids at Week 30 compared with the patients in the placebo treatment groups (22% in Remicade treatment groups vs. 10% in placebo group in study 1; 23% in Remicade treatment groups vs. 3% in placebo group in study 2). Clinical outcomes were generally similar in the Remicade 5 mg/kg and 10 mg/kg dose groups.
After positive reports in small open-label trials, the safety and efficacy of adalimumab (Humira) was assessed in a multicenter, double-blinded randomized controlled trial in patients with moderate to severe ulcerative colitis who were anti-TNF naïve and on stable suppressive therapy with oral corticosteroids and/or immunomodulators. A total of 576 patients were randomized to receive either placebo, high dose (HD), or low dose (LD) adalimumab. HD was 180/60/40/40mg and LD was 80/40/40/40mg of adalimumab at Weeks 0, 2, 4, 6, respectively. Clinical remission was defined as a Mayo score ≤ 2 with subscores no greater than 1. Secondary outcomes included absolute score decrease plus decrease in rectal bleeding subscore, proportion with mucosal healing, and proportion with mild disease (including physician global assessment [PGA], rectal bleeding, and stool frequency subscores). Because the European regulatory authorities wanted to include a LD of adlimumab, there were two parts to the study, a 1:1 with HD (n=186) and a 1:1:1 portion of the study (n=390); results were pulled from the latter.
Twice as many patients reached clinical remission at Week 8 with HD (p=0.031) therapy, while LD patients were not significantly different versus placebo. Of the secondary outcomes, subscores in rectal bleeding and PGA showed improvement with significance vs. placebo in the HD arm. Patients with higher baseline CRP levels had less instances of remission, and higher placebo rates were seen in Canadian and Eastern European centers than those in the US. Discontinuation rates were similar in each arm, with UC being the most common reason. Injection site pain was minimal and infection incidence was similar across groups, and malignancy was only seen in the placebo arm.
The safety and efficacy of golimumab (Simponi) were evaluated in two multi-center, randomized, double-blind, placebo-controlled clinical trials in patients ≥ 18 years of age (Trials UC-1 and UC-2). Trial UC-1 was an induction trial conducted in patients with moderately to severely active UC, defined as a Mayo score of 6 to 12 [the Mayo score ranges from 0 to 12 and has four subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment]. At baseline, subjects also had an endoscopy subscore of 2 or 3 on a 3-point scale (an endoscopy score of 2 is defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 is defined by spontaneous bleeding, ulceration). Patients were corticosteroid dependent (i.e., an inability to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response to or had failed to tolerate at least one of the following therapies: oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine.
Trial UC-1 was divided into 2 parts. In Part 1 (dose finding), patients were randomized to one of 4 treatment groups: 400 mg golimumab administered subcutaneously (SC) at Week 0 and 200 mg at Week 2 (400/200 mg), 200 mg golimumab SC at Week 0 and 100 mg at Week 2 (200/100 mg), 100 mg golimumab SC at Week 0 and 50 mg at Week 2 (100/50 mg), or placebo SC at Weeks 0 and 2. In Part 2 (dose confirming), 771 patients were randomized to receive either 400 mg golimumab SC at Week 0 and 200 mg at Week 2, 200 mg golimumab SC at Week 0 and 100 mg at Week 2, or placebo SC at Weeks 0 and 2. golimumab 100/50 mg SC was not evaluated in Part 2; its safety and effectiveness has not been established in UC. Concomitant stable doses of oral aminosalicylates (5-ASA), oral corticosteroids (less than 40 mg/day), azathioprine (AZA), 6-mercaptopurine (6-MP), and/or methotrexate (MTX) were permitted. Patients who received previous TNF inhibitors were excluded. The primary endpoint was the percent of patients in clinical response at Week 6, defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 (no blood seen) or 1 (streaks of blood with stool less than half the time).
Trial UC-2 was a randomized-withdrawal maintenance trial that evaluated 463 patients who achieved clinical response with golimumab induction and tolerated golimumab treatment. Patients were randomized to receive golimumab 50 mg, golimumab 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant stable doses of oral aminosalicylates, azathioprine, 6-mercaptopurine, and/or methotrexate were permitted. Corticosteroids were to be tapered at the start of the maintenance trial. The primary endpoint was the percent of patients maintaining clinical response through Week 54.
In Trial UC-1, a greater proportion of patients achieved clinical response, clinical remission and had improvement of endoscopic appearance of the mucosa at Week 6 in the golimumab 200/100 mg group compared with the placebo group. The golimumab 400/200 mg group did not demonstrate additional clinical benefit over the golimumab 200/100 mg group. Clinical remission was defined as a Mayo score ≤ 2 points, with no individual subscore > 1. Improvement of endoscopic appearance of the mucosa was defined as a Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability).
In Trial UC-2, a greater proportion of patients maintained clinical response through Week 54 in the golimumab 100 mg group compared with the placebo group. In Trial UC-2, golimumab-treated patients in clinical response (which included the subset of patients in clinical remission) in Trial UC-1, were again assessed for clinical remission at Week 30 and Week 54. A greater proportion of patients achieved clinical remission at both Weeks 30 and 54 without demonstrating a loss of response at any time point through Week 54 in the golimumab 100 mg group compared with the placebo group.
The GEMINI 1 trial tested the efficacy of vedolizumab in patients with ulcerative colitis. The study populations had a mean duration of disease of 6.9 (SD: 6.4) years and 53% of patients were on glucocorticoids with median prednisone dose of 20 mg. At week 6, 47.1% of patients in the vedolizumab arm and 25.5% of the patients in the placebo arm had a clinical response (p<0.001). In the maintenance trial, which included only those responded to the induction therapy, 41.8% of those assigned to VDZ Q8W were in clinical remission at week 52, compared with 15.9% assigned to placebo (p<0.001). Clinical remission is defined as complete Mayo score of ≤2 points and no individual subscore >1 point. Durable clinical remission was 20.5% in the VDZ Q8W group compared with 8.7% in the placebo group (p=0.008). Glucocorticoid-free remission was 31.4% in the VDZ Q8W compared with 13.9% in the placebo group (p<0.001).
Toxicities of TNF-α antagonists
All TNF-α antagonists have treatment-limiting toxicities. Some of the toxicities associated with these agents include: Concomitant use of TNF-α inhibitors and MTX consistently scored better with respect to ACR scores, disease activity in 28 joints (DAS28) scores, radiographical progression and health assessment questionnaire (HAQ) scores compared to TNF-α inhibitor monotherapy. The ACR70 scores ranged from 15-20% for all agents, with etanercept showing the highest treatment effect over the control group at 3 years in the TEMPO trial. While infliximab showed high efficacy at both 3mg/kg and 10mg/kg dosing every 8 weeks, the ACR50, ACR70 scores, HAQ scores were slightly higher with 10mg/kg dosing. The DAS28 scores and HAQ scores varied from study to study, but over-all showed improvement over controls across the TNF-α inhibitor class at 12 weeks and greater. Radiographical changes are subject to interpretation by the individual investigator, even with standardized scoring, so comparing across the TNF-α inhibitor trials is not practical. However, of the studies that did assess radiographical progression of the disease, the overall rate of radiographical progression was slowed significantly with adalimumab, certolizumab, etanercept and infliximab compared to MTX therapy alone. In the 3 year TEMPO trial, the scores for the etanercept + MTX arm showed reversal of radiographical progression, but this is debatable and requires further investigation. There is no radiographical progression data for golimumab, as they did not assess this in their clinical trials.
There have been no prospective trials evaluating safety among the TNF-α inhibitors. The risk of malignancies and serious infections has been studied to some depth retrospectively with the three older agents (adalimumab, etanercept and infliximab). The FDA did a meta-analysis of the available data in 2006 and found that the malignancy rates of patients on TNF-α inhibitors are no higher than what is to be expected in this patient population. Another study done in 2007 found a higher incidence of cutaneous cancers among the TNF-α inhibitor treated patients, irrespective of the agent. The newer agents are limited in their data breadth to demonstrate safety with respect to malignancies, but so far they compare similarly to the older agents. Long-term safety evaluations are necessary to validate this finding.
With regards to serious infections and tuberculosis, there are higher rates of serious infections while on the TNF-α inhibitors, compared to MTX alone. However, the retrospective studies do not come to an agreement on the actual risk. Infliximab showed higher rates of any infection compared to etanercept and adalimumab, and also showed higher rates of serious infections with the 10mg/kg dosing regimen versus the 3mg/kg dosing regimen. The newer agents (certolizumab and golimumab) showed increased risk of serious infections, but this data is not comparable with the older agents. This class of agents also has been associated with hepatitis B reactivation, CHF exacerbations, and new onset or exacerbation of demyelinating disorders.
The evidence suggests that etanercept and adalimumab are more cost-effective than infliximab in both early aggressive and long-standing RA. The evidence also demonstrates that combination therapy with methotrexate is more cost-effective than TNF-α inhibitor monotherapy. The majority of the published incremental cost-utility ratios fall within the willingness to pay threshold of $100,000 per quality-adjusted life year (QALY) gained, and many are less than $50,000 per QALY. The models were most sensitive to changes in drug cost. The newer agents, certolizumab and golimumab, could not be evaluated for cost-effectiveness due to lack of data.
Newer Antirheumatic Agents
Tocilizumab (Actemra®), a humanized monoclonal antibody targeted to antagonize interleukin-6 (IL-6) receptor both soluble and membrane bound, resulting in a decline of cytokine and acute phase reactant production, was approved by FDA in 2009. The inflammatory response induces the production of IL-6 from numerous synovial and endothelial cells, leading to IL-6 to congregate within the joints and mediating various other immunologic responses. Tocilizumab is indicated for moderate to severe active RA with inadequate response to one or more anti-TNF antagonist medications.
The evidence of efficacy of tocilizumab in RA consists primarily from four randomized controlled trials (RADIATE, OPTION, AMBITION, and TOWARD). The primary endpoint for all studies was the proportion of patients to reach an ACR20 response at week 24, which was achieved in all tocilizumab groups when compared to placebo. In the RADIATE trial, the 8 mg/kg, 4 mg/kg, and placebo results were 50.0%, 30.4%, and 10.1%, p<0.001. In the OPTION trial, the 8 mg/kg, 4 mg/kg, and placebo results were 59%, 48%, and 26%, p<0.0001. In the AMBITION trial, the results for the 8 mg/kg group compared to the MTX group were 69.9% and 52.5%, p<0.001. In the TOWARD trial, the results for the 8 mg/kg group compared to the DMARD placebo group was 61% and 25%, p<0.0001.
All studies showed positive secondary endpoints in the ACR50, ACR70, and remission rates defined as DAS28 score <2.6. The ACR50 scores in the RADIATE trial were 28.8% (p<0.001), 16.8% (p<0.001), and 3.8% in the tocilizumab 8 mg/kg, 4 mg/kg, and placebo group, respectively. In the OPTION trial, the ACR50 response was 44% and 31% in the 8 mg/kg and 4 mg/kg group compared to 11% (p<0.0001) in the placebo group. In the AMBITION trial, the ACR50 response for the tocilizumab group compared to the MTX group was 44.1% and 33.5% (p=0.002). In the TOWARD trial, the ACR50 response in the 8 mg/kg and placebo group was 38% and 9% (p<0.0001). No comparative effectiveness studies of this product have been reported to date.
The overall rate of serious infections with tocilizumab in the all-exposure population was 4.7 events per 100 patient-years and the overall rate of fatal serious infections was 0.13 per 100 patient-years. Because tocilizumab is the first in this therapeutic class, further long-term studies are still needed to evaluate the safety profile, and these infections are a concern.
Radiographic progression data for abatacept is now available for up to 5 years in biologic-naïve RA patients with an inadequate response to methotrexate (AIM study) and up to 2 years in methotrexate-naïve moderate to severe early RA (AGREE study). In a long-term extension of the 1-year, Phase III, randomized, double-blind, placebo-controlled AIM study, 291 of the initial 378 patients (77%), 290 (77%), 293 (78%), 287 (76%), and 235 (62%) patients had paired radiographs at baseline and at years 1, 2, 3, 4, and 5, respectively. Mean change from baseline in Genant-modified Total Sharp Score (range 0-290) was 0.80 at year 1, 0.41 at year 2, 0.37 at year 3, 0.34 at Year 4, and 0.26 at Year 5, indicating long-term inhibition of radiographic progression in biologic-naïve RA patients. In an open-label long-term extension of the 1-year, Phase III, randomized, double-blind, active (methotrexate)-controlled AGREE study, 207 biologic- and DMARD-naïve patients with moderate to severe early RA treated with the combination of abatacept and methotrexate had a mean change from baseline in Genant-modified Total Sharp Score (range 0-290) of 0.66 at year 1 vs. 1.06 (p=0.04) for the control (methotrexate alone) arm and 0.18 for abatacept + methotrexate at year 2; indicating a maintenance disease-modifying effect on bone damage over time in this population also.
Six-years of cumulative safety data integrated from 8 key clinical trials in the abatacept clinical development program were also recently reported. Cumulative experience included 11,658 patient-years in 4,149 patients, of which 1,030 patients had ≥5 years of exposure to abatacept. Mean duration of exposure was 34.2 years (range: 1.9-94.0 months). Rates were stratified by short-term (ST), long-term (LT), and cumulative exposure. The short-term period included 3,173 patients (2,331 patient-years) and the long-term period included 3,256 patients (9,278 patient-years).
The incidence rates of overall adverse events per 100 patient–years (95% confidence interval [CI]) were 386.70 (372.31–401.51) in the ST period, 228.23 (220.03–236.66) in the LT period, and 284.42 (275.50–293.55) in the cumulative period. Incidence rates of deaths and serious adverse events were low and did not increase with increased duration of abatacept exposure. The overall incidence of serious adverse events per 100 patient-years (95% CI) was 18.15 (16.41-20.02) in the ST period, 14.52 (13.66-15.43) in the LT period, and 14.82 (14.04-15.63) cumulatively. Mortality rates per 100 patient-years were 0.51 (0.27-0.90), 0.61 (0.47-0.80), and 0.60 (0.47-0.76) in the ST, LT, and cumulative periods, respectively. No increases in the annual incidence of events of special interest including rates of infections, malignancies, autoimmune events, serious cardiac events and acute infusional events were observed. Based on these data, the LT safety profile of abatacept appears consistent with its short-term safety profile.
Tofacitinib, a first-in-class oral Janus kinase inhibitor approved in 2012 for treatment of moderate to severe RA. Efficacy of tofacitinib 5 mg and 10 mg was established in five Phase III clinical trials and three Phase II dose ranging studies. All are prospective, randomized, placebo controlled, double-blind studies that conclude statistically and clinically significant improvement. Approximately twice as many patients reached ACR 20 (20% clinical improvement) in the tofacinitinib groups as placebo after 3 months of treatment. This ratio widened even more for ACR 50 and ACR 70 endpoints. Improvements in HAQ-DI and DAS28-4[ESR] scores were also statistically and clinically significant. Patients showed improvement as soon as 2 weeks. Results are consistent among the studies. In some studies, prior DMARD use and/or nonresponse were not clearly stated.Trials including an adalimumab arm suggest fairly comparable efficacy to this first line agent, but were not powered for the direct comparison.
Significant safety concerns exist for tofacitinib. The rate of serious infections, opportunistic infection, and death from serious infection was higher in the tofacitinib groups than adalimumab or placebo, even after adjusting for patient-years of treatment. Pooled data in the FDA review also identified an increased risk of lymphoproliferative disorders. Some of this may be attributable to the underlying risk of lymphoma in RA, but long-term safety is not known. Tofacitinib consistently elevates LDL and HDL cholesterol levels. Data were given as means, so individual variation in cholesterol level elevation is not available. No increase in cardiovascular events was seen in the studies, however as RA patients are already at increased risk for cardiovascular disease this is a concern. The FDA approved tofacitinib with a black box warning for infection, lymphoma, and malignancies, and testing for tuberculosis before and during treatment. Overall the long-term safety of tofacitinib is not known. As it has a novel mechanism of action, there is no long-term safety data from similar products.
Systemic Lupus Erythematosus (SLE)
The current SLE standard of care is similar across the world. Treatment of mild-to-moderate symptoms involves the use of non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial drugs such as hydroxychloroquine and corticosteroids such as prednisone and its equivalent. For life-threatening manifestations such as the renal, CNS, cardiovascular and pulmonary systems, aggressive single or combination of treatments with high dose corticosteroids and immunopressive agents such as cyclophosphamide, azathioprine, methotrexate and mycophenolate is used. Only corticosteroids, hydroxychloroquine and aspirin have FDA approved SLE indications. All others are used off-labeled for SLE.
Particularly for patients with active and life-threatening disease activity, SLE remains an unmet medical disease. The very treatments used to alleviate lupus symptoms have poor tolerability and short and long term morbidity risks. Ones used for mild/mod SLE flares involves nonspecific immune system suppression. Aggressive treatments such as cyclophosphamide is associated with gonadal toxicity, whereas high dose corticosteroids (>7.5 mg/day, cumulative doses >365g) can lead to cataracts, osteoporosis, metabolic disorders, increased infections, edema, weight gain and hyperlipidemia. This is especially concerning as SLE patients tend to be young women of child bearing age, have lower immune system and greater cardiovascular risks due to the nature of the underlying autoimmune disease. Currently there is no approved SLE treatment shown to prolong survival or reverse the course of the disease.
Belimumab is a recently FDA-approved 147kDa, recombinant fully human IgG1λ monoclonal antibody. It targets a novel pathway to potentially treat SLE by binding to soluble, endogenous human B-lymphocyte stimulator BLyS (also known as B cell activating factor or BAFF, TALL-1, THANK, TNFSF13B, zTNF4). The binding inhibits BLyS biological activity of B-cell selection, survival, differentiation and eventual antibody formation of native, activated plasmacytoid and plasma cells.
The efficacy of belimumab was studied in two Phase III trials. SLE Responder Index (SRI) response at 52 weeks, the primary endpoint, was met for belimumab 10 mg/kg treatment arm in both BLISS 52 [1.83 OR (1.30-2.59), p=0.0006] and BLISS76 [1.52 OR (1.07-2.15), p=0.0207]. Overall, secondary endpoints of reduction in severe flare, steroid use, autoantibodies, B-cell subsets, normalization of complement levels and improvement in quality of life were also achieved. 66% of the U.S. Food and Drug Administration (FDA) Arthritis Advisory Committee (10 out of 15) felt the clinical data provide support of efficacy. Concerns were cited over the lack of study consistency within and between the phase 3 studies, lack of statistical significance for some populations and the exclusion of SLE patients with severe renal or central nervous system diseases. The representative nature of the SLE patients sampled was also questioned.
The two Phase III studies were set-up nearly identically, though differences in baseline demographics, serological activity, geographical location and concurrent SLE medication use necessitate their separate analyses. Bliss 76 was conducted in North America and Europe, with 70% Caucasian and 14% African American. Relative to BLISS 52, BLISS 76 had a lower baseline SLE activity (less of SS score >=10, proteinuria>= 2g/24 hours, 1A or 2B BILAG, auto-antibodies, much less prescribed corticosteroid, while using greater NSAIDS and immunosuppressive agents). The data from BLISS 76 clinical trial was less convincing, with its more narrow incremental benefit of belimumab over placebo in SRI response, steroid use and SLE flare reduction, lack of efficacy for African American groups, and later onset of significant SS score improvement (32 weeks versus 16 weeks in BLISS 52). With the exception of African American groups, the evidence from BLISS 52 clinical trial was stronger, more robust and consistent across different ethnicities. A lower number of BLISS 52 participants receiving 10mg/kg belimumab required an increase of corticosteroids. Reduction in flares and prolongation to first flare were seen only in this ex-U.S.-conducted study.
For both studies, disease manifestation resolution often seen in organ systems were those commonly involved at baseline: mucocutaneous (rash, oral ulcers, alopecia), immunologic (serological measures of disease activity, antids-DNA and complements) and musculoskeletal (arthritis). SLE activity reduction was also observed with the vascular (vasculitis) and central nervous system (lupus headache), both systems of which were less commonly involved at study initiation. However, resolution of similarly less frequently-involved hematology abnormalities and fever was not observed in the belimumab group. The statistically significant difference in improvement from baseline as benchmarked by SRI response was driven largely by improvement of the mucocutaneous and musculoskeletal systems, and not organ systems more associated with poor SLE outcome and mortality (kidneys, central nervous system, blood vessels). Observations of these serious organ manifestations were too uncommon to assess treatment effects.
Subgroup analyses revealed a lack demonstrated efficacy in African American subjects in both Phase III studies, which contradicted the positive treatment response previously observed in LBS02 Phase II trial. Similarly, Native Americans were found more associated with favorable disease activity reduction in BLISS 52 but not its counterpart trial. There was some geographical dependence, as participants from U.S. and Canada had smaller treatment effect compared to some other regions. Since belimumab is to be administered chronically, durability and onset of response are of concern. Of note, differences in efficacy endpoint at the conclusion of BLISS 76 were no longer statistically significant between treatment arms [PLO 32%, 10mg/kg 39%, 1.3 (0.9, 1.9), p=0.13], which was a drop from PLO 34%, 10mg/kg 43% 1.5 (1.07, 2.15), p=0.0207 in the preceding 24 weeks. Dose-response was not consistent; throughout the studies, 1mg/kg was noticed at times to be more, or just as, effective as the more potent proposed formulation. Patients with severe renal or central nervous system (CNS) diseases were not evaluated and therefore efficacy not known. A disclaimer to this effect was included in the final approved product label. (See Indications section.)
As safety data were pooled from the three intravenous belimumab clinical studies (LBS02, BLISS 52 and BLISS76) in an attempt to generate a sufficiently large sample of rare events, the ability to detect safety trend concerning specific ethnicity and geological populations was lost. Overall, headache, upper respiratory tract infection and arthralgia were some of the common adverse events experienced by belimumab participants. Pyrexia was the most reported serious adverse event. The investigational drug was found associated with greater risk of infection, mortality and psychiatric events ranging from depression, suicidal ideation to suicide. Notably, no such neuropsychiatric adverse events were seen in those receiving only SLE standard therapy. Malignancy and hypersensitivity rates were comparable to the placebo group. While belimumab has safety signals, its safety profile is favorable and relatively minor compared to the side effects experienced by those on current SLE standard-of-care. 14 of the 15 Advisory Committee members agreed that the clinical data provided adequate safety evidence. However, it is worthwhile to mention that belimumab has not been studied in children under 18 of age and limited pharmakinetics data is available on the elderly population.
B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line. Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in the non-lymphoid tissues examined.
The beneficial effects of Rituximab in active SLE, refractory to standard immunosuppression, have been reported in 24 case series from specialized lupus centers throughout the world. There is a consistency of reported improvement across all case series, despite use of different end points. Use of Rituximab in this setting is recommended by the May 2012 American College of Rheumatology guidelines, as well as the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association recommendations for the management of adult and pediatric lupus nephritis published November 2012. There have been two RCTs of Rituximab in SLE, the LUNAR (Lupus Nephritis Assessment with Rituximab) and EXPLORER (Exploratory Phase II/III SLE Evaluation of Rituximab) studies, which enrolled 144 and 257 patients with non-renal and renal disease respectively. Although neither study achieved their primary end-point, it is recognized that there were important design limitations in these trials, including issues with end-point measurements, the very high use of concomitant steroids in combination with other immunosuppressives in both treatment arms, as well as being underpowered to detect a clinically meaningful improvement. The clinical trials added rituximab on top of standard therapy for non-refractory patients. Patients who had failed standard therapies were excluded, as were those with severe organ-threatening manifestations. Despite these limitations, pre-specified secondary analyses did suggest efficacy of rituximab in several patient subsets, including significantly fewer (p< 0.01) patients in the rituximab group requiring cyclophophosphamide for worsening disease. There were also serological improvements, with significant effects on anti-dsDNA antibodies and complement levels. Both these tests are sensitive bloodstream markers of lupus-specific disease activity Improvement in these parameters is known to be a predictor of clinical response, and also support biological efficacy of rituximab.
Recent open-label studies strongly support the clinical efficacy of rituximab particularly in the group of refractory SLE populations. Lu et al. studied 50 patients, and of 45 patients with adequate follow-up, 19 (42%) achieved remission at the 6 month time point Li et al. studied patients with lupus nephritis treated with rituximab with or without cyclophosphamide. Of the 19 patients recruited 4 (21%) had a complete response at 48 weeks using the SLICC Renal Response Criteria. 11 (58%) had a partial response and 4 patients (22%) were stable or worsened at 48 weeks. A case series of 164 patients with biopsy proven lupus nephritis from England and Spain, the majority of whom had refractory or relapsing disease, reported a complete or partial response (>50% improvement in all renal parameters) in 67% of patients at 6 months after rituximab. A recent systematic analysis of studies in refractory lupus nephritis (300 patients) reported a complete or partial response in 67- 87% of patients, according to lupus nephritis subtype. Similarly, a meta-analysis of 188 patients from open-label studies noted an overall 91% response rate within the cases reported and even an 89.3% response in patients with CNS involvement. Efficacy has also been reported amongst 136 patients in the French Autoimmunity and Rituximab registry of patients with both renal and non-renal disease, with improvements in articular, cutaneous, renal and hematologic manifestations. Although there are important limitations of open-labeled studies, the overall experience of the use of rituximab in refractory lupus is that there is a definite efficacy of this agent in patients that have failed conventional combination therapy (corticosteroids, hydroxychloroquine and immunosupressants). While the magnitude of improvement in individual patients is variable, there is clear evidence that rituximab offers an important therapeutic option for people living with severe SLE that has been refractory to existing conventional therapies.
Idiopathic Thrombocytopenic Purpura (ITP)
Longer courses of corticosteroids may be preferred over shorter courses of corticosteroids or IVIg as first-line treatment. IVIG may be used in addition to corticosteroids when a more rapid increase in platelet count is required. Either IVIG or anti-D (in appropriate patients) may be used as a first-line treatment if corticosteroid are contraindicated. The criteria for using Intravenous Immune Globulin (IVIG) to treat ITP are addressed separately in another medical policy. (See Related Policies). The use of rituximab and human thrombopoietin (TPO) agents are not recommended in the initial treatment of ITP. Rituximab may be considered for treatment of chronic adult ITP or in those who are unresponsive to or relapse after initial corticosteroid therapy or have failed splenectomy. FDA-approved agents are romiplostim (Nplate®), a subcutaneously injected thrombopoietic agent that increases platelet production in a dose-dependent manner by binding to and activating the human thrombopoietin (TPO) receptor, and eltrombopag (Promacta®), an oral, small-molecule TPO-receptor agonist that binds to the transmembrane domain of the human TPO-receptor to initiate signaling cascades to induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. The optimal treatment for patients requiring second-line therapy is uncertain. Guidelines and expert opinions have not reached consensus due to the lack of comparative clinical and economical data. This policy is based on ASH 2011, which is a well-established evidence-based guideline. Selection of a treatment option should take into consideration the individual patient’s bleeding risk, activity level, likely side effects of treatment and patient preferences. This guideline and several other expert reviews support the use of rituximab as a second line treatment option for patients with ITP who have failed at least one other therapy such as corticosteroids, IVIG, or splenectomy. Because there is no evidence to guide the sequence of treatments, it is no longer required that a patient fail thrombopoietin (TPO) receptor agonists in order to be eligible for rituximab.
Efficacy of eltrombopag
There are three published clinical trials evaluating the efficacy and safety of eltrombopag in chronic idiopathic thrombocytopenic purpura (ITP). A Phase II pivotal study showed that significantly more subjects treated with eltrombopag 50 mg (70%) and 75 mg (81%) responded to therapy compared to placebo (11%) (P < 0.001). About one third of the subjects used concomitant ITP medications during the study, and one half of the subjects were splenectomized. Although it was noted that response was higher in those treated with concomitant medications, stratified results for these subgroups were not presented. Bleeding events were only considered as secondary endpoints, and the results showed that subjects treated with eltrombopag 30 mg and 50 mg showed fewer signs of bleeding than placebo, but subjects treated with eltrombopag 75 mg showed increased signs of bleeding.
Another Phase III pivotal trial showed that the primary endpoint of response, defined as subjects who had an increase in platelet counts to ≥ 50,000/µL at week six, was reached in 58.9% of those treated with eltrombopag versus 16.2% of those receiving placebo (P <0.001). Additionally this study showed that the odds of responding were significantly higher in the eltrombopag group versus the placebo group (P <0.001). Response to eltrombopag was not statistically significantly affected by concomitant treatment (P = 0.766), prior splenectomy (P = 0.747) or having baseline platelet counts below 15,000/µL (P = 0.453). Bleeding events were considered as a secondary endpoint and significantly fewer events took place in the eltrombopag group versus placebo (39% and 60%, respectively; P = 0.029), however the trial was not powered to detect such differences.
An ongoing, Phase III extension trial (EXTEND) evaluating the long-term efficacy of eltrombopag showed that 50% of enrolled subjects had a continuous response (platelet count ≥ 50,000) for more than four weeks, 35% for at least 10 weeks, and 24% for more than six months. At the one-year time point, only 7% of patients still showed response. A summary of this study in the manufacturer’s dossier states that 48% of patients were able to discontinue or reduce concomitant ITP medications, and that bleeding events were significantly reduced for eltrombopag-treated patients. Since data from this study is only available in post-hoc reviews, it is not yet possible to evaluate the validity or usefulness of these results.
Efficacy of romiplostim
In the published RCT of romiplostim for the treatment of chronic ITP, a statistically significant response was achieved by subjects treated with romiplostim (49%) compared to placebo (2%) (P < 0.0001). Romiplostim also showed a statistically significant reduction in the dependence on rescue medication (21.7%) compared to placebo (59.5%) (P < 0.0001). Limitations of this study include that all participants were allowed use of concurrent ITP medications, and the results were not stratified to demonstrate the effect of these medications on the results. Additionally, the primary endpoint of this study was to determine the platelet response of patients to romiplostim, whereas bleeding events were a secondary endpoint. It would have been more clinically relevant if the study would have been specifically powered to determine the difference in bleeding events between romiplostim and placebo- treated subjects.
There is an ongoing, open-label extension study to evaluate the long-term safety and efficacy of romiplostim in subjects who had previously completed a romiplostim trial. The primary endpoint is platelet response, defined as a platelet count of ≥ 50,000/µL. Throughout the study, 18 subjects never met the primary endpoint, but 10 of those still continued with the treatment. After a sharp increase in platelet counts during the first four weeks, platelet counts generally remained stable or gradually increased through week 144. The study reported platelet responses of 30% after the first dose and 51% after the third dose. Subjects that responded had a response during 67% of the weeks enrolled in the study. The results reported do not include any raw numbers, but are reported solely as percentages, except for the instance of those that showed a response at least once. This study lacks definitive information to demonstrate that a response to romiplostim once or continually will result in prevention of adverse events or improve mortality and morbidity.
No head-to-head trials have been conducted between eltrombopag or romiplostim and other agents used to treat chronic ITP, such as IVIg, anti-D, or rituximab. Five small uncontrolled studies were found reporting response rates generally in the 30-40% range. These are classified as case series and are considered Level C evidence. No head to head studies versus romiplostim, eltrombopag or IVIG were found.
Safety of eltrombopag and romiplostim
The evidence for the safety of eltrombopag and romiplostim is based on clinical studies, which are considered to be Level B evidence. Although eltrombopag and romiplostim have shown to have mostly mild side effects, rare but serious adverse reactions have been reported. The safety of eltrombopag and romiplostim seem to be similar, however some additional adverse events have occurred in patients treated with one or the other medication.
Bone marrow reticulin formation and risk for bone marrow fibrosis have been associated with the use of eltrombopag and romiplostim. TPO-receptor agonists increase the risk for formation or progression of reticulin fiber deposition within bone marrow. Peripheral blood smears have confirmed the presence of bone marrow reticulin formation in both the eltrombopag and romiplostim clinical trials. Prior to the initiation of these medications, peripheral blood smears must be obtained and examined to establish a baseline level of cellular abnormalities, and obtained along with complete blood counts (CBCs) monthly after the initiation of either.
Worsened thrombocytopenia and increased risk of bleeding has been associated with the cessation of eltrombopag and romiplostim. Thrombocytopenia may be of greater severity than prior to initiation of either agent, which can increase the risk of bleeding. The increased risk of bleeding may be particularly apparent in patients on anticoagulants or antiplatelet agents. Follow-up studies of both medications have indicated that the rebound effect is transient, but CBCs with platelets should be obtained weekly for at least two weeks following discontinuation.
Thrombotic/thromboembolic events may occur from excessive increases in platelet counts, associated with excessive doses of eltrombopag and romiplostim. To minimize this risk, these medications should not be administered to normalize platelet counts. Caution should be used when administering either medication to patients with known risks for thromboembolism.
Development and progression of hematological malignancies have been observed in patients treated with eltrombopag or romiplostim, due to the stimulation of the TPO-receptor on the surface of hematopoietic cells. This risk may be particularly important in myelodisplastic syndrome. These agents should not be used to treat any thrombocytopenia other than ITP.
Eltrombopag carries a Black Boxed Warning for hepatotoxicity. Hepatotoxicity was one of the most commonly reported severe adverse events in patients treated with eltrombopag. Hepatotoxicity has not been reported in patients treated with romiplostim, likely due to the lack of first pass metabolism because it is administered IV. Grade 4 liver abnormalities were reported in patients treated with eltrombopag in randomized controlled trials (RCTs), whereas none were reported in patients treated with placebo. ALT, AST, and bilirubin should be measured prior to the initiation of eltrombopag, every two weeks during dose titration, and monthly after a stable dose has been established. Abnormal tests should be repeated within three to five days, and if confirmed, serum liver tests should be monitored weekly until they resolve. Eltrombopag should be discontinued if ALT levels reach ≥ three times baseline and are progressive, persistent for ≥ four weeks, or are accompanied by increased direct bilirubin, clinical symptoms of liver injury or evidence for hepatic decompensation.
Cataracts have developed or worsened in some patients treated with eltrombopag. Eltrombopag was shown to cause cataracts in pre-clinical trials of rodents. Ocular examinations should be performed prior to the initiation of eltrombopag, and patients should be regularly monitored for signs and symptoms of cataracts during treatment.
A lack or loss of platelet response has been demonstrated in patients treated with romiplostim. Patients who are hyporesponsive or fail to respond should be evaluated for causative factors, including formation of neutralizing antibodies or bone marrow fibrosis. Blood samples should be submitted to Amgen for assay to determine antibody formation against romiplostim or TPO. Romiplostim should be stopped after four weeks on the highest dose (10µg/kg) if sufficient platelet levels have not been achieved to avoid clinically important bleeding.
Eltrombopag and romiplostim are only available through restricted distribution programs, Promacta CARES and NEXUS, respectively. Only prescribers and patients who enroll in these programs and understand the risks of therapy are eligible to prescribe, obtain, administer, and receive these medications. Prescribers are required to understand the information in the prescribing information and be able to educate patients on the risks and benefits, provide the medication guide, and encourage questions regarding the use of the medication. Adverse events must be actively solicited every six months, and be reported to the drugs’ respective program.
Efficacy and Safety of Rituximab
Rituximab has gained its popularity amongst hematologists because of its curative and spleen sparing potential. The efficacy of rituximab in treating adult patients with ITP who have failed one or more lines of therapy including splenectomy came from a large systematic review (19 studies, 313 patients) by Arnold and colleagues. They reported that rituximab had an overall platelet response rate of 62.5% (95% [CI] 52.6%−72.5%) and a median duration of 10.5 months (range 3–20). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy. However, the durability of rituximab is not as impressive. Long-term response longer than one year has been reported to be between 18% and 35%.
Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, Phase II trial, 60 patients with chronic ITP who have failed one or more previous treatments received rituximab infusions and were followed for up to 2 years. Forty percent of patients (95%CI 28%–52%) achieved platelet count ≥ 50,000/µL at 1 year, and 33.3% at 2 years. Based on these results, rituximab could be used as a presplenectomy therapeutic option, particularly in patients who are at increased surgical risk or who are reluctant to undergo surgery. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy- sparing agent in ITP.
Safety outcomes were also reported by Arnold et al from pooled data of 306 patients. They found that 3.3% (10 patients) had severe or life-threatening complications and 2.9% (9 patients) had died after rituximab treatment.
Recently Progressive multifocal leukoencephalopathy has emerged as a serious complication of rituximab treatment. Although rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.
New Oral Agents for Multiple Sclerosis
Fingolimod is an oral modulator of sphingosine-1-phosphate receptor. After absorption, fingolimod is phosphorylated and fingolimod phosphate acts as agonist on the sphingosine-1-phosphate-1 receptors of the lymphocyte and thymocytes. This interaction results in the internalization of the receptor and thus without signaling the lymphocytes become sequestered within the lymph nodes. It is hypothesized that the resulting decrease in circulating lymphocytes then leads to fewer lymphocytes entering the CNS. Additionally, it is also hypothesized that when fingolimod crosses the BBB the resulting binding down modulates the S1P in neural cells and thus there is a reduction in the astrogliosis that can lead to neurodegeneration. Fingolimod has not been shown to inhibit the effector functions of T and B cells, humoral immunity, or virus-specific cytotoxic T cells. (18)
The efficacy of fingolimod was demonstrated by two Phase III randomized placebo-controlled trials. Fingolimod was found to be significantly better than placebo at the strength of 0.5 mg at reducing the annualized relapse rate, MRI assessment measures, and disease progression measurements. The primary endpoint was reduction in annualized relapse rate over 24 months was 0.18 (0.15-0.22) for 0.5 mg fingolimod and 0.40 (0.34-0.47) for placebo with a p-value <0.001. This represents a 54% relative reduction in relapses as compared to placebo. Disease progression confirmed after 6 months had a probability of 12.5% for 0.5 mg fingolimod versus 19% for placebo. (13)
Fingolimod was compared to IM interferon beta-1a in one clinical trial. Fingolimod proved superior in the primary endpoint of annualized relapse rate. The ARR for fingolimod 0.5 mg was 0.16 (0.12-0.21) versus 0.31 (0.22-0.41) for interferon beta-1a with a p-value <0.001. Additionally, fingolimod was superior in the secondary endpoint of T1 lesion amount. For fingolimod 0.5 mg the mean volume was 22.61±111.59 versus 50.68±198.16 for interferon beta-1a with a p-value of <0.001. However, fingolimod did not prove superior at prevention of disease progression as compared to interferon beta-1a. (14)
Overall, fingolimod has a reasonable safety profile. There is a potential for bradycardia or AV block after administration of the first dose that may require monitoring. Additional concerns are potential increased susceptibility to infections, macular edema, and lymphopenia. The only deaths that occurred during the clinical trial were in the 1.25mg fingolimod arm and suffered a herpes zoster and herpes simplex encephalopathy infections respectively. (15-17)
Dimethyl fumarate, (Tecfidera) is a newly approved oral agent that is indicated for the treatment of relapsing forms of MS (RMS). The exact mechanism whereby it exerts its therapeutic effects is unknown. However, dimethyl fumarate and its metabolite, monomethyl fumarate (MMF), activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in cellular response to oxidative stress and implicated in regulation of myelin maintenance in the central nervous system. In vitro, MMF has also been identified as a nicotinic acid receptor agonist.
Well designed and adequate evidence consistently supports the efficacy of dimethyl fumarate at approved dosing for reduction of relapse and improving neuroradiologic outcomes over 2 years in patients with relapsing-remitting MS. Whether the agent is “disease modifying” or delays disease progression is unclear because of the conflicting results for 12-week confirmed disability progression from the two registrational Phase III trials.
After two years therapy in the placebo-controlled phase III trials, the most common adverse events were mostly mild to moderate flushing and GI events (nausea, vomiting, and abdominal pain). Incidence of these events was highest in the first month of use and then generally decreased thereafter. Discontinuation due to AEs was similar to that for placebo. Excepting for relapse of MS, SAEs were reported very infrequently. Mean lymphocyte counts decreased approximately 30% during the first year of treatment with dimethyl fumarate then levels plateaued. However, incidence of infections and serious infections were similar between patients receiving the drug and those receiving placebo. Elevations in aminotransferase levels were also observed. In the phase IIb study, transaminase elevations were considered dose related.
abatacept injection (Orencia®) for rheumatoid arthritis
Injection, adalimumab (Humira), 20mg
Injection, alefacept (Amevive), 0.5mg
Injection, certolizumab pegol, 1 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
Injection, certolizumab pegol, 1 mg (deleted 12/31/14)
Injection, etanercept (Enbrel), 25mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
Injection, infliximab (Remicade), 10mg
Injection, belimumab, 10 mg
Injection, natalizumab, (Tysabri), 1mg
Injection, romiplostim, 10 mcg (Nplate)
Injection, tocilizumab, 1 mg
Injection, ustekinumab (Stelara), 1mg.
Prescription drug, oral nonchemotherapeutic, NOS (Promacta, generic – Eltrombopag)
Injection, rituximab, 100 mcg (Rituxan, generic rituximab)
New policy. This policy is added to the Prescription Drug section addressed prescription drug medications used to treat autoimmune disorders. The policy replaces previously active policies which have now been deleted: 5.01.526; 5.01.531; 5.01.600; 5.01.601; and 5.01.602.
Coding update; ICD-9 procedure code 99.29 and diagnosis codes 714.0 and 714.2 removed. These are not utilized for adjudication of the policy; informational only.
Update Related Policies. Add 5.01.521.
Interim review. Additional agent added to the policy: Psoriasis: PDE4 Inhibitors; apremilast (Otezla®) may be considered medically necessary for the treatment of adult patients with psoriatic arthritis when ALL of the criteria are met. References 211 – 221 added.
Interim review. Vedolizumab (Entyvio™) added for the treatment of Crohn’s and ulcerative colitis; supportive information added to the Rationale section. References 222-224 added. Correction made to therapeutic drug class table. CPT codes and HCPCS J7050 removed from policy; these do not suspend and are not reviewed at this time.
Coding correction. HCPCS code J0717 added to the policy. This code replaced J0718 as of 1/1/14 and appeared on policies 5.01.601 and 5.01.602; it should have been carried over to this policy at the time it was originally effective.
Interim review. Policy updated with a new Otezla® indication for plaque psoriasis. Reference 22 added; 24 and 25 updated.
Annual review. Drug table within the Policy section updated to include indications for treatment of Pyoderma Gangrenosum: first line, Humira® and Enbrel®; and, second line, Remicade®.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).